FLUORO KETONE INHIBITORS OF HYDROLYTIC ENZYMES
FLUORO KETONE INHIBITORS OF HYDROLYTIC ENZYMES
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DOI：
10.1021/bi00329a001
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发表时间：
1985-01-01
期刊：
影响因子：
2.9
通讯作者：
ABELES, RH
中科院分区：
文献类型：
--
作者：
GELB, MH;SVAREN, JP;ABELES, RH
研究生院生物化学系，布兰迪斯大学，沃尔瑟姆，马萨诸塞州02254接收于1985年2月4日摘要：研究了氟酮作为水解酶抑制剂的用途。乙酰胆碱类似物6，6-二甲基-1，1，1-三氟-2-庚酮和3，3-二氟-6，6-二甲基-2-庚酮是乙酰胆碱酯酶的抑制剂，Ki值分别为16 × 10 - 9 M和1.6 × 10 - 9 M。这些氟代酮作为抑制剂比相应的甲基酮好1005倍。由于亲核试剂容易与氟酮加成，因此这些化合物可能通过与活性位点丝氨酸残基形成稳定的半缩酮来抑制乙酰胆碱酯酶。氟酮底物类似物也是锌金属蛋白酶和锌酰基蛋白酶的抑制剂。2-苄基-4-氧代-5，5，5-三氟戊酸是羧肽酶A的抑制剂（-= 2 X™ 7 M）。三氟甲基酮二肽类似物是良好的血管紧张素转换酶抑制剂。已经制备了一种胃蛋白酶抑制剂类似物，它含有一个二氟他汀残基代替他汀，并发现它是一种非常有效的胃蛋白酶抑制剂（K = 6 × 10 ~（11）M）。水合酮可能是抑制物质，因为它们是肽底物水解过程中形成的四面体中间体的结构模拟物。
Graduate Department of Biochemistry, Brandéis University, Waltham, Massachusetts 02254 Received February 4, 1985 abstract: The use of fluoro ketones as inhibitors of hydrolytic enzymes has been investigated. The acetylcholine analogues 6, 6-dimethyl-1, 1, 1-trifluoro-2-heptanone and 3, 3-difluoro-6, 6-dimethyl-2-heptanone are inhibitors of acetylcholinesterase with K {values of 16 X 10~ 9 M and 1.6 X 10™ 9 M, respectively. These fluoro ketones are lOMO5 times better as inhibitors than thecorresponding methyl ketone. Since nucleophiles readily add to fluoro ketones, it is likely that these compounds inhibit acetylcholinesterase by formation of a stable hemiketal with the active-site serine residue. Fluoro ketone substrate analogues are also inhibitors of zinc metallo-and aspartylproteases. 2-Benzyl-4-oxo-5, 5, 5-trifluoropentanoic acid is an inhibitor of carboxypeptidase A (í¡= 2 X™ 7 M). Trifluoromethyl ketone dipeptide analogues are good inhibitors of angiotensin converting enzyme. An analogue of pepstatin that contains a difluorostatone residue in place of statine has been prepared and found to be an extremely potent inhibitor of pepsin (K¡= 6 x 10™ 11 M). The hydrated ketones are probably the inhibitory species since they are structural mimics of the tetrahedral intermediate that forms during the hydrolysis of peptide substrates.